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Las Plagas, literally meaning "The Plagues" in Spanish, is a breed of parasitic organisms. Unlike the T-Virus, which turned its victims into mindless zombies, the victims of Las Plagas (such as the Ganados and Majini) become much stronger and highly resistant to pain, while working collectively to pursue their targets. Another side effect is the loss of higher reasoning, except in select subjects (who still are unable to shake off the need to obey higher orders) and the full compliance to the Control Plaga.
Las Plagas were first discovered by a religious cult in Europe known as "Los Illuminados" in an unnamed rural region of Spain and used the Plagas as a means of recruiting new members. However, the first castellan of the Salazar family opposed the cult and sealed off access to the parasites in his castle.
However, centuries later, the eighth Salazar castellan, Ramon Salazar, was convinced by Osmund Saddler, the new leader of Los Illuminados, to join Los Illuminados and open the seal that concealed the Plagas. The two employed the local villagers to excavate the parasites.
When they unearthed them, the Plagas parasites seemed dead due to years of confinement and many were fossilized in the rocks below Salazar's castle. However, the Plagas were still alive at the microscopic level in spores within the fossils and these spores were inhaled by the miners hired to extract them, giving birth to the parasites within their bodies. Saddler later obtained the means to recreate the parasites wholly, injecting them in egg form into potential hosts to turn them into Ganado.
With the Plagas parasites, Saddler managed to take control of the entire nearby village and its chief, Salazar's castle, and an island that he used to host his private military. While most were injected with regular Las Plagas, Saddler and his top underlings (Ramon Salazar, Bitores Mendez, and Jack Krauser) wielded the Dominant Species Plaga or Control Plaga, allowing them to keep their free will and command the regular infected Ganado.
Albert Wesker, who was leading the remnants of the Umbrella Corporation, sent two of his agents, Ada Wong and Jack Krauser, to retrieve the sample of the Control Plaga. Krauser became a henchman to Saddler himself and was sent to kidnapping the U.S. President's daughter, Ashley Graham. Though Krauser succeeded in his mission Saddler didn't give Krauser the sample, prompting Wesker to sent Ada to infiltrate the Ganado-controlled territory and obtain the sample by force. The U.S. Government meanwhile sent in special agent Leon S. Kennedy to rescue Ashley by any means needed. During this mission, Leon was attacked by the Plagas-infected Villagers, but Ada rang the Church's bell which made the Villagers retreat from Leon.
In the Church, Leon rescued Ashley and encountered Osmund Saddler, who revealed he had the two implanted with Las Plagas. To escape, Leon went to confront Bitores Mendez at the Slaughterhouse to obtain the False Eye, the Village Gates' key, from him. After killing Mendez Leon stole his eye.
Leon later went to Salazar's castle, where he encountered the Zealots, the most fanatical members of Los Illuminados. After fighting them off, Leon and Ashley found themselves faced by Ramon Salazar, who wanted to kill Leon and recapture Ashley Graham. When Ashley fell into one of the traps Leon went to the other side to rescue her. There, Leon met Luis Sera, a non-infected Humans, who attempted to give Leon the vaccines only to be killed by Saddler and have the vaccines stolen from him. Leon then found Ashley, who had been taken by a Novistador and brought to Salazar. Leon confronted Salazar at one of the towers and learned that Ashley was moved to an island Leon then fought and defeated Salazar along with his Verdugo Bodyguard.
Following this Leon traveled to the Island and pursued Ashley's trail. He managed to catch up to her but she was taken by Saddler. Leon is then confronted by Krauser and discovers he was the one who kidnapped Ashley. After dueling Krauser in a knife fight Krauser escapes and IT is unleashed to fight Leon, but Leon kills the beast. Leon then finds Krauser again, killing him and then rescuing Ashley for the final time.
Ada attempted to fight Saddler herself but was captured and tied up. However, Leon then fought Saddler and defeated him with the assistance of Ada, who threw Leon a Special RPG. However, after Saddler was defeated, Ada held Leon at gunpoint to obtain the Control Plaga. Once she had gotten it she escaped via Helicopter to deliver the Plaga to a true organization she served instead of Wesker. Leon and Ashley meanwhile escaped the Island via jet ski before it blew up from the bombs. However, Wesker was able to obtain the Control Plaga from Krauser's body himself, allowing him to control Las Plagas-infected ones.
Wesker infects the population of Kijuju, Africa to turn them into puppets for himself and his TRICELL associates, Excella Gionne and Ricardo Irving. BSAA agents Chris Redfield and Sheva Alomar soon showed up to contain the outbreak and were attacked by the Plaga-controlled Majini. However, Chris and Sheva escaped Kijuju with the help of Dave Johnson and arrived at the Wetlands.
Chris and Sheva found Irving in the Oil Fields, guarded by large numbers of Majini. After defeating him on his boat during his escape, the two head towards a Cave where they are faced with the tribal Majini. They later find Excella is a Research Facility and pursue her, leading the team to a confrontation with Wesker and the controlled Jill Valentine. While Wesker and Excella escaped, Jill was restored to normal thanks to the duo who then followed Wesker.
The agents pursued Wesker onto the TRICELL-owned Ship, where they were attacked a large number of Majini Soldiers. They soon were confronted by Excella who transformed into Uroboros to fight them but the agents defeat her. Chris and Sheva then went to fight Wesker and crashed his Bomber ship into a volcano, where Albert used Uroboros to battle the two. With assistance from Jill Valentine and Josh Stone, Chris and Sheva finally defeat Wesker with two RPGs. Following Wesker's demise, the four escaped via Helicopter.
- Las Plagas might have been a reference to the Pod People from the "Invasion of the Body Snatchers" film, because the Pod People take control of their host's body and socialize with other infected hosts, much like what the Plagas does.
- All lower level Ganados are shown to have lost their need for personal hygiene, due to the observations Leon makes in the first few chapters of the game and various water sources throughout the game.